What is insulin resistance?

What is Insulin Resistance?

Insulin resistance is a pathophysiological state where target tissues (primarily liver, skeletal muscle, and adipose tissue) exhibit diminished responsiveness to physiological levels of insulin, resulting in impaired glucose uptake and utilization despite normal or elevated insulin concentrations. 1

Core Pathophysiology

Insulin resistance represents a defect in the cellular response to insulin at one or more points in the complex pathways of hormone action, occurring in the postreceptor signal transduction pathways. 1 This means:

• The insulin receptor may bind insulin normally, but the downstream cellular machinery fails to respond appropriately 1
• Deficient insulin action results from diminished tissue responses to insulin, not necessarily from inadequate insulin secretion initially 1
• The body compensates by producing more insulin (hyperinsulinemia) to maintain normal blood glucose levels 1, 2

Critical Clinical Distinction

Insulin resistance can exist even when blood glucose levels are completely normal (normoglycemia), and it precedes the development of glucose abnormalities by years. 2, 3 This is a crucial point often missed in clinical practice—normal glucose readings do not exclude insulin resistance 3.

Affected Tissues and Metabolic Consequences

The primary insulin-responsive tissues affected include:

• Skeletal muscle: Impaired glucose uptake and utilization 4
• Liver: Decreased suppression of glucose production (hepatic glucose output) and increased de novo lipogenesis leading to dyslipidemia 1, 4
• Adipose tissue: Reduced glucose uptake and impaired suppression of lipolysis, leading to elevated free fatty acids 1

The Compensatory Response and Progression

Initially, pancreatic β-cells compensate for insulin resistance by secreting more insulin (hyperinsulinemia), maintaining normal blood glucose levels. 1, 2 However:

• As long as the pancreas can adequately compensate, blood glucose remains normal despite underlying insulin resistance 1
• Over time, β-cell function may deteriorate, leading to β-cell failure 1
• When insulin secretion becomes insufficient to overcome the resistance, impaired glucose tolerance develops 2
• Eventually, this progression can lead to type 2 diabetes mellitus 2

Underlying Mechanisms

Several mechanisms contribute to insulin resistance development:

• Ectopic lipid accumulation in liver and skeletal muscle interferes with insulin signaling 5
• Genetic abnormalities in proteins of the insulin action cascade, including insulin receptor mutations (though rare) 1
• Postreceptor signaling defects where the lesion resides in signal transduction pathways downstream of the insulin receptor 1
• Endoplasmic reticulum stress and chronic inflammation in target tissues 5
• Visceral adiposity releasing dysregulated metabolic mediators (adipokines, cytokines, excess lipids) that promote insulin resistance in other tissues 6, 7

Clinical Context and Associated Conditions

Insulin resistance is the central pathogenic feature of multiple metabolic abnormalities, collectively termed the "Insulin Resistance Syndrome" or "Metabolic Syndrome," which includes 8, 7:

• Type 2 diabetes mellitus 1
• Obesity, particularly central/visceral adiposity 1, 3
• Hypertension 8
• Dyslipidemia (elevated triglycerides, low HDL cholesterol) 1
• Cardiovascular disease 1, 8
• Polycystic ovary syndrome (PCOS) 8, 7
• Metabolic dysfunction-associated fatty liver disease (MAFLD) 6

Important Clinical Caveats

A transient insulin-resistant state occurs normally during puberty, peaking at mid-puberty due to increased growth hormone, sex hormones, and insulin-like growth factor-1 levels, then returning to near-prepubertal levels by the end of puberty 1. This physiological insulin resistance should not be confused with pathological insulin resistance.

Certain rare genetic syndromes cause severe insulin resistance through insulin receptor mutations, including Type A insulin resistance (with acanthosis nigricans), leprechaunism, and Rabson-Mendenhall syndrome 1. These represent extreme forms but illustrate the spectrum of insulin resistance severity.

Various hormones antagonize insulin action, and their excess can precipitate or worsen insulin resistance, including growth hormone (acromegaly), cortisol (Cushing's syndrome), glucagon (glucagonoma), and epinephrine (pheochromocytoma) 1, 3. This typically occurs in individuals with preexisting defects in insulin secretion 1.